Structural mechanisms for ?-conotoxin activity at the human ?3?4 nicotinic acetylcholine receptor.

ABSTRACT: Nicotinic acetylcholine receptors (nAChR) are therapeutic targets for a range of human diseases. ?-Conotoxins are naturally occurring peptide antagonists of nAChRs that have been used as pharmacological probes and investigated as drug leads for nAChR related disorders. However, ?-conotoxin interactions have been mostly characterised at the ?7 and ?3?2 nAChRs, with interactions at other subtypes poorly understood. This study provides novel structural insights into the molecular basis for ?-conotoxin activity at ?3?4 nAChR, a therapeutic target where subtype specific antagonists have potential to treat nicotine addiction and lung cancer. A co-crystal structure of ?-conotoxin LsIA with Lymnaea stagnalis acetylcholine binding protein guided the design and functional characterisations of LsIA analogues that identified the minimum pharmacophore regulating ?3?4 antagonism. Interactions of the LsIA R10F with ?4 K57 and the conserved -NN- ?-conotoxin motif with ?4 I77 and I109 conferred ?3?4 activity to the otherwise inactive LsIA. Using these structural insights, we designed LsIA analogues with ?3?4 activity. This new understanding of the structural basis of protein-protein interactions between ?-conotoxins and ?3?4 may help rationally guide the development of ?3?4 selective antagonists with therapeutic potential.

SUBMITTER: Abraham N 

PROVIDER: S-EPMC5374441 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature